PROJECT SUMMARY/ABSTRACT Survival from Head and Neck Squamous Cell Carcinoma (HNSCC) is poor, and a racial disparity between African Americans (AfAm) and European Americans (EuAm) has been consistent for decades. From 2008-2014, 5-year relative survival from oral cavity and pharyngeal cancers is reported to be 49.4% among AfAms in contrast to 66.6% among EuAms. Similarly, 5-year relative survival for laryngeal cancer was 51.3% among AfAms in contrast to 61.8% among EuAms. The literature suggests that poor survival may be related to late-stage diagnosis that is attributed to lower screening rates, socioeconomic status (SES) and other barriers to care. However our preliminary data suggest that these factors alone may not provide a complete explanation. We have shown that the risk of recurrence, second primary cancer or metastasis was higher for AfAm compared to EuAm after matching patients on age and smoking dose and adjusting for sex, family history of cancer, alcohol use, SES, insurance, stage at diagnosis, and treatment modality. These findings suggest that other than clinical and socioeconomic factors, host factors such as genetics may also contribute to survival disparities. Standard treatment of HNSCC utilizes combined-modality therapy that involves DNA damaging agents such as radiotherapy (RT) and platinum-based chemotherapy (PbC). A reduction of treatment sensitivity to DNA damaging agents are often attributed to repair of DNA lesions by DNA damage response (DDR) genes expressed in cancer tissues. We performed genomic analyses of tissues from oral cavity and laryngeal cancer (OCLxC) patients in The Cancer Genome Atlas (TCGA). The impact of genetic ancestry on gene expression of DDR genes was evaluated in 316 patients. After adjusting for gene methylation, copy number variation and population stratification, five ancestry informative markers (AIMs) were associated with altered mRNA expression of the DDR gene Polymerase ? (POLB) where 1) higher expression of POLB was observed among AfAm patients in comparison to EuAm patients and 2) patients treated with RT/PbC with one or two African ancestry alleles (homozygous or heterozygous genotypes) at these genetic loci had lower overall survival (~21%) and disease- free survival (~22%) in contrast to patients with both European ancestry alleles at these genetic loci. Elevated expression of POLB modulates cellular DNA repair capacity and DNA replication that would provide tumor resistance to RT/PbC. Therefore we will test the hypothesis that genetic ancestry contributes to differences in expression of POLB resulting in differences in survival between Black and White OCLxC patients treated with RT/PbC, mediated by enhanced nuclear and mitochondrial DNA repair capacity and an oncogenic-like replicative state due to POLB over expression. Using novel approaches that involve molecular epidemiology combined with basic tumor cell and molecular biology, we will confirm our preliminary findings, investigate the functional significance of genetic ancestry on POLB expression and on survival disparities between AfAm and EuAm OCLxC patients.